Cocaine is the most frequently reported illicit drug used by patients presenting to emergency rooms in the U.S.. The clinical course of these patients is often complicated by trauma, the need for emergent surgical intervention, and drug toxicity. Thus, anesthesiologists have a critical and increasing role in the acute care of these patients. Cocaine intoxication produces recurrent seizure activity that is often resistant to standard anticonvulsant therapy and can ultimately lead to permanent neurological damage and even death. This central nervous system (CNS) excitotoxicity may be due to the drug's inhibition of sodium conductance as well as to the inhibition of monoamine reuptake, resulting in increased extracellular amino acid and monoaminergic neurotransmitter concentrations in specific CNS pathways. Moreover, it has been well established that the susceptibility to this CNS excitotoxicity is often amplified with chronic use of the drug. The basis for this increased susceptibility may be related to alterations in extracellular CNS monoaminergic and amino acid neurotransmitter release following repeated exposure to the drug. There is a paucity of scientific information regarding the effect of anesthetic drugs on the CNS excitotoxicity of cocaine. Consequently, microdialysis and electroencephalographic techniques will be employed in a chronically instrumented rat model, following acute and chronic cocaine exposure, in order to determine the effect of anesthetic drugs (fentanyl and dexmedetomidine) on: 1) cocaine-induced epileptiform activity and 2) extracellular dopaminergic and glutamatergic neurotransmitter concentrations in the nucleus accumbens (NAC) of the brain, an area linked to the behavioral and excitatory effects of cocaine. We hypothesize that anesthetic agents modify the CNS excitatory effects of cocaine by altering extracellular dopaminergic and glutamatergic neurotransmitter concentrations in the NAC. This information will provide a fundamental understanding of the interaction between commonly used anesthetic drugs and cocaine in terms of modification of central neurotransmitter concentrations and CNS excitotoxicity. This information is essential if we are to better understand the anesthetic management of cocaine-abusing patients and may also be relevant to the many patients taking psychiatric medications, drugs that also alter CNS dopaminergic and glutamatergic activity. This award will allow me to obtain the investigational skills and knowledge base that will enable me to develop into a clinician-scientist and independent investigator in anesthesiology and neuroscience research.